Original compounds useful in cancer therapy are subject of interest in industrial and academic laboratories [Avendano, C., Menendez, J. C. (2008) Medicinal Chemistry of Anticancer Drugs, Elsevier Science, 1st edition].
Malignant tumor diseases are the most frequent cause of death [Siegel R. et al. (2012), CA Cancer J. Clin. 62, 10-29]. The uncontrolled cellular growth is linked to inherited genetic factors as well as environmental factors. For initiation and development of a malignant disease, the accumulation of several various genetic or epigenetic changes is necessary. This leads to transformation of a healthy cell into a fully malignant phenotype [Stratton M. R. (2011), Science 331, 1553-1558]. Cumulation of gene mutations leads to perturbations in normal functioning of proteins encoded by these genes. The proteins take part mainly in the regulation of cell division and differentiation, in the control of DNA replication fidelity, in the regulation of apoptosis of the damaged cells, in intercellular communication and intracellular signaling pathways [Hanahan D., Weinberg R. A. (2000), Cell 100, 57-70]. Malignant cells, unlike benign cells, have the ability to penetrate into the surrounding healthy tissue (invasiveness). Cancer cells are can be released from the original tumor and spread through the bloodstream or lymphatic system to distant parts of the body to form new tumors (metastatic process) [Nguyen D. X. et al. (2009), Nat. Rev. Cancer 9, 274-284].
The aim of anticancer therapy is to selectively induce apoptosis in the undesirable cancer cells, while not affecting the surrounding healthy tissue. Cytotoxic therapeutics act through DNA damage or microtubule damage and their specificity towards tumor cells in human body is due to their ability to selectively kill fast-proliferating cells. This selectivity can be determined by their cytostatic effects in cell culture in vitro [Chabner B. A., Roberts T. G (2005), Nat. Rev. Cancer 5, 65-72; Lüllmann H. et al. (2005), Farmakologie a toxikologie, Grada, 15th edition].
The fact that tumor cells are derived from cells of a host organism is a limiting factor for achieving the maximal selectivity of the cytotoxic effect. The sensitivity of cancer cells towards treatment is determined by the growth fraction of a tumor (the ratio of proliferating and non-proliferating tumor cells), the site of action of the cytostatic agent within the cell cycle, and the natural and the acquired resistence of the tumor cells against the cytostatics.
The present invention opens a straightforward way for obtaining novel compounds, structurally belonging to the helquat family and useful as therapeutics for diseases related to increased cellular proliferation.
Recently, papers describing synthesis of helical extended diquats (helquats) have been published [Adriaenssens et al. (2009), Chem. Eur. J. 15, 1072-1076; Severa et al. (2010), Tetrahedron 66, 3537-3552; Vavra et al. (2012), Eur. J. Org. Chem. 489-499]. They represent a new and therefore unexplored class of compounds with dicationic helical skeleton. The basic helquat skeletons described heretofore are composed so that each skeleton contains two quaternary N-heteroaromatic units which introduce two positively charged centers into the system, e.g. in the form of pyridinium, quinolinium, or isoquinolinium cationic moieties. Hence, a typical helquat arrangement is associated with dicationicity and with helical chirality at the same time. This combination has not been studied before in the context of small aromatic organic molecules.
A disadvantage of the heretofore described synthesis of these compounds was a limited variability due to the need for assembling each compound in a multistep synthesis de novo. The present invention overcomes this disadvantage, as it introduces not only novel helquat derivatives, but also method of preparation thereof by one-step diversification of methyl-substituted helquats using Knoevenagel condensation with substituted or non-substituted arylaldehydes.